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Heiss, C. et al.

Mutation of cysteine-295 to alanine in secondary alcohol dehydrogenase from Thermoanaerobacter ethanolicus affects the enantioselectivity and substrate specificity of ketone reductions.

The mutation of Cys-295 to alanine in Thermoanaerobacter ethanolicus secondary alcohol dehydrogenase (SADH) was performed to give C295A SADH, on the basis of molecular modeling studies utilizing the X-ray crystal structure coordinates of the highly homologous T. brockii secondary alcohol dehydrogenase (1YKF.PDB). This mutant SADH has activity for 2-propanol comparable to wild-type SADH. However, the C295A mutation was found to cause a significant shift of enantioselectivity toward the (S)-configuration in the reduction of some ethynylketones to the corresponding chiral propargyl alcohols. This result confirms our prediction that Cys-295 is part of a small alkyl group binding pocket whose size determines the binding orientation of ketone substrates, and, hence, the stereochemical configuration of the product alcohol. Furthermore, C295A SADH has much higher activity towards t-butyl and some alpha-branched ketones than does wild-type SADH. The C295A mutation does not affect the thioester reductase activity of SADH. The broader substrate specificity and altered stereoselectivity for C295A SADH make it a potentially useful tool for asymmetric reductions.[1]

References

Mutation of cysteine-295 to alanine in secondary alcohol dehydrogenase from Thermoanaerobacter ethanolicus affects the enantioselectivity and substrate specificity of ketone reductions. Heiss, C., Laivenieks, M., Zeikus, J.G., Phillips, R.S. Bioorg. Med. Chem. (2001) [Pubmed]

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